Our long-term goal is to improve patient care in scleroderma and other interstitial lung diseases involving lung injury/fibrosis. While scleroderma is frequently thought of as a skin disease, in most patients it spreads to the lungs and other internal organs. This lung disease is devastating, results in a poor quality of life, is the most frequent cause of death in scleroderma, and has no FDA-approved treatment. Studies on lung tissue and blood cells from human patients and from animal lung disease model systems indicate that a common feature of interstitial lung diseases is the under expression in several cell types of caveolin-1, a protein that acts as a master regulator of several signaling pathways. It is particularly intriguing that both monocytes and fibroblasts are deficient in caveolin-1 because a portion of the fibroblasts present in fibrotic tissues are derived from bone marrow progenitors via the Bone Marrow Cell -> Monocyte -> Fibrocyte -> Fibroblast lineage. The identification of caveolin-1 as a key target in interstitial lung disease was validated using the caveolin-1 scaffolding domain (CSD) peptide, a peptide which mimics the function of full-length caveolin-1. In particular, CSD inhibits the overexpression of the chemokine receptor CXCR4 by scleroderma monocytes and their extremely active migration toward the CXCR4 ligand CXCL12. In vivo in the mouse bleomycin model system, CSD inhibits fibrosis, the overexpression of CXCR4 by monocytes, and monocyte and fibrocyte infiltration into damaged lung tissue. In summary, these observations suggest the hypothesis that a major role for caveolin-1 in the pathogenesis of interstitial lung diseases is in the regulation of CXCR4 expression, function in cell migration, and signaling in cells of the bone marrow -> monocyte -> fibrocyte lineage. To test this idea, we will: 1) Determine the mechanisms through which caveolin-1 regulates CXCR4 levels, function, and signaling and thereby regulates the trafficking of monocytes and fibrocytes; 2) Determine whether CXCR4/CD14/TLR4 receptor complexes differ in prevalence and function in Normal and SSc monocytes and the role of caveolin-1 in complex formation and function; and 3) Perform in vivo experiments to: Determine the function of caveolin-1 in regulating the trafficking of bone marrow-derived cells to the lungs via the blood and their phenotype and function, and to Promote the development of CSD as a drug for human patients. These studies will provide important, novel mechanistic details on the regulation by caveolin-1 of the function of cells in the fibrocyte lineage which play central roles in fibrotic diseases of the lungs and other organs. This information will further validate CSD as a novel treatment for these currently untreatable diseases and justify studies developing this treatment. This is of the utmost urgency because there are currently no effective treatments for scleroderma and other interstitial lung diseases.